ALPHA SYNUCLEIN IN MODELS OF MSA

多系统萎缩（MSA）的主要病理特征是在少突胶质细胞中发现的胶质细胞质包涵体（GCI）。GCI的主要成分是α -突触核蛋白。在一系列将在过表达α -突触核蛋白的转基因（tg）小鼠系中进行的研究中，我们将研究似乎有助于α -突触核蛋白积累和聚集的因素。具体目标我们假设，在某些神经启动子的控制下，过表达h[α]-synuclein的tg小鼠会在少突胶质细胞和/或神经元中积累h[α]-synuclein，并可能导致gci样改变的形成。我们已经建立了一个tg小鼠系，其中h[α]-synuclein是

The cardinal pathological feature of multiple system atrophy (MSA) is the glial cytoplasmic inclusion (GCI), which is found in oligodendrocytes. A major component of the GCI is alpha-synuclein. In a series of studies, which will be carried out in transgenic (tg) mouse lines overexpressing alpha-synuclein, we will examine factors that appear to contribute to the accumulation and aggregation of alpha-synuclein. Specific Aim 1. We hypothesize those tg mice overexpressing h[alpha]-synuclein under the control of certain neural promoters will accumulate h[alpha]-synuclein in oligodendrocytes and/or neurons and may result in formation of GCI-like alterations. We have established a tg mouse line, in which h[alpha]-synuclein is overexpressed under the control of the platelet-derived growth factor B (PDGF-B) promoter, and these tg mice demonstrate motoric deficits and accumulation of h[alpha]-synuclein in oligodendrocytes and neurons. We have established a tg mouse line in which alpha-synuclein is targeted to be overexpressed in only oligodendrocytes by placing the h[alpha]-synuclein transgene under the control of the myelin basic protein (MBP) promoter. Both strains of tg mice will undergo detailed behavioral, neurochemical and neuropathological analyses. Specific Aim 2. We hypothesize that oxidative stress favors the accumulation of h[alpha]-synuclein. To study the effects of these factors, both strains of tg h[alpha]-synuclein mice will be crossed with superoxide dismutase (SOD) 1, SOD 2 and glutathione peroxidase knockout mice. The animals will undergo analyses as in Specific Aim 1. Specific Aim 3. We hypothesize that nitration favors the accumulation of h[alpha]-synuclein. To study the effects of these factors, both strains of tg h[alpha]-synuclein mice will be crossed with neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS) knockout mice. The animals will undergo analyses as in Specific Aim 1.